Novel Pathways for Kidney Stone Formation

项目总结/摘要 肾结石很常见，治疗费用高，而且很痛苦，还可能导致许多慢性疾病的发生。 尽管在肾结石形成机制和危险因素的识别方面取得了进展， 在过去的一年里，肾结石预防诊所对患者的评价和管理发生了变化。 20年此外，肾结石复发率仍然居高不下。我们提出的目标是 研究的目的是为结石形成的发病机制提供新的见解， 制定新的治疗和/或预防策略。 我们建议善用第二期护士健康研究和医护专业人员的资源， 随访研究（HPFS），正在进行的队列研究，随访时间长达数十年， 生物储存库数据，进行第一次大规模的基于人群的肠道研究（N = 800）。 微生物组和肾结石（目标1），并执行第一个前瞻性，血浆和尿液代谢组学- 基于肾结石形成的研究（N = 1200）（目的2）。 肠道微生物群可能通过改变肾结石的吸收和随后的代谢而在肾结石形成中发挥作用。 尿排泄各种致石因子。一项小型研究报告了一种独特的肠道微生物组， 与对照组相比，结石形成者。然而，肠道植物群的差异是否有助于 或者代表已确定的肾结石危险因素的微生物“标记”， 和身体大小。在目标1的病例对照研究中，我们将使用NHS II的粪便样本来确定肠道 肾结石患者的微生物分类学和宏基因组功能生态学， 饮食和体型我们还将研究肠道微生物组与24小时尿液之间的关系 混合物. 在NHS II和HPFS（目标2）的前瞻性、巢式病例对照研究中，我们将使用最先进的液体 或气相色谱法，然后是质谱分析平台，以从血浆中鉴定> 1300种代谢物 和尿液。在有针对性的代谢组学分析中，我们将确定循环性别之间的独立关联， 激素、微生物衍生代谢物和肾结石风险。在非靶向代谢组学分析中，我们寻求 发现与肾结石形成相关的新代谢物特征。我们将使用本金 成分分析和其他先进的统计方法，以建立独特的代谢物签名， 测定血浆和尿液代谢物数据以区分肾结石病例和对照。

PROJECT SUMMARY/ABSTRACT Kidney stones are common, costly, and painful, and may lead to the development of many chronic diseases. Despite advances delineating mechanisms of kidney stone formation and identifying risk factors, little has changed in the evaluation and management of the patient in the kidney stone prevention clinic during the last 20 years. Furthermore, kidney stone recurrence rates remain stubbornly high. The goal of our proposed studies is to provide new insights into the pathogenesis of stone formation that eventually will lead to the development of new treatment and/or prevention strategies. We propose to leverage the resources of the Nurses' Health Study II (NHS II) and the Health Professionals Follow-up Study (HPFS), ongoing cohort studies with decades of follow-up and rich dietary, lifestyle, and biorepository data, to conduct the first large-scale population based study (N = 800) of the intestinal microbiome and kidney stones (Aim 1), and to perform the first prospective, plasma and urine metabolomics- based study (N = 1200) of kidney stone formation (Aim 2). Intestinal microbiota may play a role in kidney stone formation by altering the absorption and subsequent urinary excretion of a wide variety of lithogenic factors. A small study reported a distinct gut microbiome in stone formers compared with controls. However, it is unknown whether differences in intestinal flora contribute to stone formation or instead represent microbial `markers' of established kidney stone risk factors such as diet and body size. In our case-control study in Aim 1, we will use stool samples from NHS II to define the intestinal microbial taxonomic and metagenomic functional ecologies in individuals with nephrolithiasis, independent of diet and body size. We also will examine associations between the intestinal microbiome and 24-hour urine composition. In prospective, nested case-control studies within NHS II and HPFS (Aim 2), we will use state-of-the-art liquid or gas chromatography followed by mass spectrometry platforms to identify > 1300 metabolites from plasma and urine. In targeted metabolomic analyses, we will identify independent associations between circulating sex hormones, microbial derived metabolites, and kidney stone risk. In untargeted metabolomic analyses, we seek to discover novel metabolite signatures associated with kidney stone formation. We will use principal component analysis and other advanced statistical methods to build distinct metabolite signatures that use all the measured plasma and urine metabolite data to distinguish kidney stone cases from controls.